The ability to discriminate self from non-self (foreign) is one of the hallmarks of the immune response. Diseases such as autoimmune gastritis (AIG) have been attributed to a breakdown of the normal state of T-cell tolerance to tissue-specific self proteins. Experimental AIG can be initiated by T-cells reactive to the parietal cell-specific antigen-H+/K+-ATPase. This recognition of antigens localized to the gastric parietal cell can explain the damage to the parietal cells in AIG, but it does not provide any explanation for the loss of zymogenic cells or the gain of mucous cells and hyperproliferative cells which are a hallmark of both human and murine disease. We have now generated a novel experimental model of AIG to test our hypothesis that it is a secondary non-antigen specific phage of immune mediators which leads to the striking tissue-specific histopathologic changes that characterize AIG. This model utilizes transgenic mice which express human growth hormone (hGH) exclusively in a subset of the gastric parietal cell population of the stomach and are functionally tolerant to this hGH transgenic reporter. We now demonstrate that this tolerance can be ablated by immunization with hGH, resulting in antigen-specific T cell proliferation, antibody production, and altered epithelial architecture in the zymogenic glands of the stomach. This novel model of gastrointestinal autoimmune disease is ideally suited to investigate to what extent the contribution of T-cells is due to specific immune recognition events versus non antigen-specific events. In this grant application, we propose to: 1) establish a lymphocyte transfer model of AIG in a transgenic mouse by utilizing a T-cell mediated anti-self (transgene) immune response; and 2) define the cellular and molecular mechanisms critical in the direct or indirect effects of T-cells in tissue- specific gastric epithelial damage. These studies should result in a well- defined artificial model of autoimmune gastrointestinal disease, and will lead to a more detailed understanding of the cellular and molecular events underlying the tissue-specific pathogenesis of human gastric inflammatory disease.